PROJECT SUMMARY Malignant tumors are considered ?unresectable? if they are adhere to vital structures or the surgery would cause irreversible damages to the patients and impair their quality of life. Such solid tumors can arise from a variety of cancer types including prostate, lung, colon, pancreatic, liver, ovarian, head and neck, and others. Also, for patients with metastatic cancers, the resection may cause considerable morbidity since they have already been weakened by their metastatic diseases, chemotherapy, and/or radiation therapy. In order to prevent the tumor growth or provide complete tumor resolution without surgery, a variety of cytotoxic drugs and radiation therapies are currently in clinical practice. Unfortunately, severe adverse side effects are usually associated with these therapeutic modalities. Since these tumors are already locally advanced or have begun to metastasize, the outlook today for these cancer patients is bleak and survival rate remains very low. The goal of this project is to develop a clinically practical internal radiation therapy for more efficient treatment of unresectable solid tumor cancers with significant reduction of adverse side effects. Recently, we have developed a synthesis process to produce hollow gold nanoparticle-based core/shell structures, which can be directly translated into a unique radiolabeling methodology for metal nanoplatforms to be used as radiotherapeutic agents of cancer. We incorporated palladium-103 (103Pd), a radioisotope currently in clinical brachytherapy, into a hollow gold nanoparticle. The resulting 103Pd@Au nanoparticles in the form of a colloidal suspension can be administered by direct injection into tumors, serving as internal radiation sources (nanoseeds) for radiation therapy. The size of the nanoseed, ~150nm in diameter, is large enough to prevent nanoseeds from diffusing into other areas while still small enough to allow them to homogeneously distribute inside the tumor. We further performed a preliminary experiment to test the therapeutic efficacy of 103Pd@Au nanoseeds when intratumorally injected into a prostate cancer (PCa) xenograft model. Remarkably, we observed an averaged tumor burden reduction of 80% as compared to control groups. Given the promising potential of such therapeutic agents shown by our preliminary, we propose here to further optimize and test this technology towards its clinical application. If successful, it will open up many possible applications of nanoseed-based internal radiation therapy, potentially providing an alternative therapeutic modality for unresectable solid tumors with significantly reduced side effects.